Diastereoselectivity in the cycloaddition of 1-benzyl-2-piperazinone nitrone with alkenes

Article abstract of DOI:10.1055/s-2004-834955

The diastereoselectivity of the [2 + 3]-cycloaddition of 1-benzyl-2-piperazinone nitrone with several alkenes has been examined. exo-Type cycloadducts predominated for most substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-834955

PAPER
465
Diastereoselectivity in the Cycloaddition of 1-Benzyl-2-piperazinone Nitrone
with Alkenes
D
iastereoselectiv
o
ity in the
C
y
n
cloaddition
o
a
f
1-Benzyl-
l
2-pipe
d
razinone
N
itrone
w
C
ith
A
lkenes . Bernotas,*1 Lily Sing, Dirk Friedrich
Aventis Pharmaceuticals, Box 6800, Route 202-206, Bridgewater, NJ 08807, USA
Fax +1(484)8659399; E-mail: BERNOTR@wyeth.com
Received 30 July 2004; revised 18 September 2004
OCH3
H
H
Abstract: The diastereoselectivity of the [2 + 3]-cycloaddition of 1-
benzyl-2-piperazinone nitrone with several alkenes has been exam-
ined. exo-Type cycloadducts predominated for most substrates.
N
+
N
O
Ar
H3CO
O
Key words: cycloadditions, diastereoselectivity, heterocycles, sub-
stituent effects, bicyclic compounds, nitrone, alkenes
5
6
7
Scheme 2
Nitrone cycloadditions are powerful reactions for the as-
sembly of complex structures.2 Our own interest in ni-
trones both as radical scavengers3 and as intermediates for
medicinal agents led us to synthesize nitrone 1. This ni-
trone readily underwent [2 + 3] cycloaddition reactions
with alkynes and alkenes to give isoxazolines and isox-
azolidines, respectively.4 These cycloadducts provided
access to 3-substituted 2-piperazinones which served as
precursors to more complex heterocyclic systems such as
constrained aryl piperazine 4 (Scheme 1).5 While our ini-
tial work focused primarily on substrates in which
diastereomeric product mixtures were not possible, cyclo-
addition with unsymmetrical alkenes could produce dia-
stereomers. For example, reaction of 1 with silyl enol
ether 2 gave a 7:1 ratio of 3a and 3b, respectively. Our de-
sire to introduce substituents on the 2-piperazinone side-
chain, with stereochemical control, led us to investigate
the diastereoselectivity of the cycloaddition of nitrone 1
with a variety of unsymmetrical alkenes.
mer, which arises from an exo-type addition, was carried
on to ( )-elaeocarpine and ( )-isoelaeocarpine.
Tamura and coworkers reported good to excellent diaste-
reoselectivity in the reaction of chiral nitrone 8 with a va-
riety of alkenes to give cycloadducts 9 as the major or
exclusive stereoisomer (Scheme 3).8 Again, exo-mode ad-
dition predominated. Cleavage of the morpholinone ring
in 9 removed the chiral auxiliary to reveal an amino acid.
From these reports, we expected to observe high diaste-
reoselectivity favoring exo-mode addition in the cyclo-
addition of 1 with unsymmetrical alkenes.
O
O
H
O
N
O
H
H
H
+
Ph
N
C6H6
Ph
X
O
H
X
O
9
8
R
N
Scheme 3 X = O, NR¢
O
F
OTMS
R
N
O
NR
H
Nitrone 1 was prepared in a straightforward manner
(Scheme 4).4 Protected 2-piperazinone 10 was alkylated
with benzyl bromide to afford 11 which was deprotected
with neat TFA to provide 12. The secondary amine was
oxidized regioselectively to nitrone 1 using hydrogen per-
oxide with sodium tungstate as a catalyst.9 Although sta-
ble at ambient temperatures for at least several months,
nitrone 1 readily reacts with monosubstituted alkenes un-
der very mild conditions. Typically, the reactions were
run in dichloromethane for 2–4 days at ambient tempera-
tures using a 3:1 ratio of alkene–nitrone. In the case of 1-
hexene, additional alkene was added. The reaction mix-
tures were simply concentrated in vacuo and purified by
flash chromatography to afford isoxazolidines 13–19.
Diastereomeric mixtures were separable by this method.
N
2
R1
R2
N
N
O
O
1
3a R1 = OTMS, R2 = Ar
3b R1 = Ar, R2 = OTMS
4
Scheme 1 R = CH2Ph
Diastereoselectivity in the reaction of cyclic nitrones and
alkenes has been extensively investigated by other work-
ers.6 In an early example, Tufariello and Ali obtained a
single product 7 from the cycloaddition of 1-pyrrolidine
1-oxide (5) with styrene (6) (Scheme 2).7 This diastereo-
The [2 + 3] cycloadditions gave good to excellent yields
and only one regioisomer was isolated. The high regiose-
lectivity is well precedented in related nitrone reactions
SYNTHESIS 2005, No. 3, pp 0465–0469
Advanced online publication: 08.12.2004
DOI: 10.1055/s-2004-834955; Art ID: M05504SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

466
R. C. Bernotas et al.
PAPER
R
N
NR
R
N
R
H3C
O
NR
O
N
O
O
c
a, b
N
O
H
H
H
HO
CH2Cl2
N
H
H
1
O
N
N
N
H
O
O
Boc
H
H
O
H3C
HOH2C CH3
1
10 R = H
11 R = CH2Ph
12
19b
Scheme 4 a) NaH–DMF–PhCH2Br; b) TFA; c) Na2WO4·2 H2O–
Scheme 6 R = CH2Ph
30% H2O2–EtOH
ene, hydrogen-bonding effects apparently favored an
and is consistent with HOMO–LUMO arguments made endo-type addition. Applications of nitrone 1 are currently
by others.10 In reactions using simple hydrocarbons such under investigation.
as styrene and 1-hexene, the cycloaddition was highly dia-
stereospecific. Based on the NOE pattern exhibited by the
Reaction solvents were Aldrich anhyd grade except for CH2Cl2,
isoxazolidine protons, the relative stereochemical assign-
ments of the newly formed asymmetric centers were as
shown for styrene in Scheme 5. The diastereomer pro-
duced for each of the hydrocarbon substrates was that ex-
pected from an exo-mode of addition, consistent with the
well-precedented preference of cyclic nitrones for this
mode of addition.6–8
which was obtained from EM Sciences and used as received. Mps
were determined using a Thomas–Hoover apparatus and are uncor-
rected. 1H NMR spectra were obtained on Varian Gemini-300, Uni-
ty-300 and Unity-400 spectrometers. Chromatography refers to
flash chromatography on silica gel.
4-Benzyl-3-oxopiperazine-1-carboxylic Acid tert-Butyl Ester
(11)
A stirred solution of 1011 (10.01 g, 50.0 mmol) in anhyd DMF (50
mL) under nitrogen was treated with benzyl bromide (6.00 mL, 50.0
mmol). Sodium hydride (60% in an oil dispersion, unwashed, 2.00
g, 50.0 mmol) was added in portions over 10 min. Gas and heat
evolved. After 18 h, Et2O (400 mL) and H2O (200 mL) were added
to the reaction mixture and the layers were separated. The ethereal
layer was washed with H2O (100 mL) and brine (100 mL) and then
dried (MgSO4), suction filtered and concentrated in vacuo to a white
solid. This product was stirred with hexanes (100 mL) for 30 min,
and then suction filtered. The white solid was air-dried and then
vacuum-dried to afford 11.
NR
O
NR
H
H
N
O
styrene
CH2Cl2
N
1
O
NOE
NOE
H
H
H
O
H
Ph
H
Ph
H
13
Scheme 5 R = CH2Ph
The cycloaddition of nitrone 1 with hydroxy-bearing sub-
strates was also investigated. Slightly lower diastereose-
lectivity was observed with allyl alcohol and with its one
carbon homolog, 3-buten-1-ol, although the product re-
sulting from an exo-mode addition still predominated.
This slight erosion in selectivity may have arisen from hy-
drogen bonding between the substrate hydroxy group and
the nitrone oxygen, which would tend to reverse the ori-
entation of the alkene and thus enhance endo-mode addi-
tion. In the final cycloaddition, 3-hydroxy-2-methyl-1-
propene was chosen as a hydroxy-bearing substrate in
which the steric requirements of the alkene substituents
are more balanced. With the steric effects minimized, the
contribution of the hydroxy group to diastereoselectivity
should be enhanced. In this case, the endo-mode of cy-
cloaddition was favored (13:87 ratio of 19a–19b) indicat-
ing hydrogen bonding played a major role in determining
the facial selectivity (Scheme 6). The reaction still pro-
ceeded in high yield.
Yield: 10.8 g (37.2 mmol, 74%); mp 85–87 °C.
IR (KBr): 1701, 1688, 1643, 1425, 1248, 1171 cm–1.
1H NMR (CDCl3): d = 7.38–7.26 (5 H), 4.62 (2 H, s), 4.16 (2 H, s),
3.58 (2 H, app. t, J = 5.4 Hz), 3.25 (2 H, app. t, J = 5.3 Hz), 1.45 (9
H, s).
13C NMR (CDCl3): d = 165.7, 153.8, 136.1, 128.7, 128.2, 127.7,
80.6, 49.9, 47.8 (br), 45.5, 40.1 (br), 28.3.
MS (CI; CH4): m/z (%) = 291 (10), 263 (20), 235 (100).
Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65. Found: C,
66.33; H, 7.77; N, 9.68.
1-Benzylpiperazin-2-one (12)
Compound 11 (10.7 g, 36.9 mmol) in a flask cooled to 0 °C was
treated with TFA (40 mL). Gas evolved. After 20 min, the reaction
was concentrated in vacuo at ca. 40 °C and the resulting viscous liq-
uid was carefully treated with sat. aq NaHCO3 (150 mL). Gas
evolved. Additional solid NaHCO3 was added until gas evolution
had ceased and the solution was basic (pH ca. 9). The reaction mix-
ture was diluted with H2O (ca. 50 mL) and extracted with 40–60
EtOH–CH2Cl2 (4 × 250 mL). The combined extracts were washed
with H2O (50 mL), dried (Na2SO4), and concentrated in vacuo to
give 12 as a viscous liquid.
In conclusion, we have shown that the cycloaddition of ni-
trone 1 with several alkenes proceeded regiospecifically.
High diastereoselectivity was observed in cycloadditions
of the nitrone with mono-substituted alkenes lacking a hy-
droxy group, consistent with exo-mode addition. The
diastereoselectivity decreased somewhat for mono-
substituted alkenes, allyl alcohol and 3-buten-1-ol, while
for the more sterically balanced geminally substituted alk-
Yield: 5.95 g (31.3 mmol, 85%).
IR (CHCl3): 1636 cm–1.
1H NMR (CDCl3): d = 7.38–7.25 (5 H), 4.60 (2 H, s), 3.59 (2 H, s),
3.22 (2 H, app. t, J = 6.5 Hz), 3.03 (2 H, app. t, J = 6.5 Hz), 1.83 (1
H, br s).
Synthesis 2005, No. 3, 465–469 © Thieme Stuttgart · New York

PAPER
Diastereoselectivity in the Cycloaddition of 1-Benzyl-2-piperazinone Nitrone with Alkenes
467
Table 1 Diastereoselectivity of the Reaction of Nitrone 1 with Alkenes
Entry
1
Alkene
Reaction
time (h)
Cycloadducts (R = CH2Ph)
Ratio
Combined
yield (%)
exo
endo
exo–endo
72
not detecteda
>98:2a
87
R
N
O
H
N
O
Ph
13
2
3
90
not detecteda
>98:2a
90
H3CO
R
N
O
H
N
O
Ar
14
72
90
48
not detecteda
not detecteda
R
>98:2a
>98:2a
92:8
91
91
92
R
N
O
H
N
O
CH2Ph
15
4
5
R
N
O
H
N
O
(CH2)3CH3
16
HO
HO
R
N
O
H
N
O
H
N
O
N
O
CH2OH
CH2OH
17a
R
N
17b
6
7
48
48
96:4
95
90
R
O
H
N
O
H
N
O
N
O
CH2CH2OH
CH2CH2OH
18a
18b
13:87
R
N
R
CH3
O
H
N
O
H
HO
N
O
N
O
CH3
CH2OH
CH3
CH2OH
19a
a Proton NMR showed essentially one diastereomer.
19b
13C NMR (CDCl3): d = 167.8, 136.6, 128.6, 128.1, 127.4, 50.3, 49.7,
as a viscous oil with trace contaminants by TLC analysis. This prod-
uct partially solidified on standing. Trituration with Et2O (ca. 100
mL) afforded 1.
47.1, 43.1.
MS (CI; CH4): m/z (%) = 191 (100).
Yield: 4.40 g (21.6 mmol, 70%); very slightly yellow solid; mp 72–
73 °C.
1-Benzyl-4-oxy-5,6-dihydro-1H-pyrazin-2-one (1)
To a stirred solution of 12 (5.88 g, 30.9 mmol) in EtOH (150 mL)
was added Na2WO4·2 H2O (0.50 g, 1.54 mmol), aq hydrogen perox-
ide (30%; 7.0 mL, 68 mmol), and H2O (7.5 mL). After 6 h, the re-
action mixture was treated with brine (75 mL) and extracted with
CH2Cl2 (2 × 150 mL). The combined extracts were dried (MgSO4),
filtered through a pad of Na2SO4, and concentrated in vacuo. The
crude product was purified by flash chromatography [EtOAc and
then EtOH–EtOAc (10:90) to give 1 (5.13 g; Rf ca. 0.25 in EtOAc]
IR (KBr): 1649, 1566, 1217 cm–1.
1H NMR (CDCl3): d = 7.38–7.25 (5 H), 7.19 (1 H, s), 4.65 (2 H, s),
4.01 (2 H, t, J = 6.3 Hz), 3.53 (2 H, t, J = 6.5 Hz).
13C NMR (CDCl3): d = 159.1, 135.5, 129.0, 128.2, 128.2, 58.7, 49.1,
42.0.
MS (EI): m/z (%) = 204 (100), 132 (85), 91 (100).
Synthesis 2005, No. 3, 465–469 © Thieme Stuttgart · New York

468
R. C. Bernotas et al.
PAPER
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.67; H, 5.90; N, 13.66.
MS (CI; CH4): m/z (%) = 323 (100), 203 (35).
5-Benzyl-2-butyltetrahydroisoxazolo[2,3-a]pyrazin-4-one (16)
An additional portion of 1-hexene (0.37 mL, 3.0 mmol) was added
after 42 h. The crude product was purified by chromatography
(EtOAc) (to remove a small amount of unreacted nitrone 1) to give
16.
Cycloaddition of Nitrone 1 with Alkenes; General Procedure
A stirred solution of alkene (3.00 mmol) in CH2Cl2 (2.0 mL) under
nitrogen at r.t. (ca. 18 °C) was treated with nitrone 1 (204 mg, 1.00
mmol). The reaction mixtures were concentrated in vacuo when
TLC analysis using EtOAc as eluent indicated complete (or near
complete) consumption of nitrone. Reaction times were as shown in
Table 1. The residue after concentration was purified by flash chro-
matography to give the products. Ratios of diastereomers were de-
termined based on isolated products.
Yield: 263 mg (91%); Rf ca. 0.52 in EtOAc); off-white solid; mp
89–90 °C.
IR (KBr): 2935, 1637, 1499, 1454, 1264, 700 cm–1.
1H NMR (CDCl3): d = 7.35–7.22 (5 H), 4.69 (1 H, d, J = 14.6 Hz),
4.50 (1 H, d, J = 14.6 Hz), 4.23 (1 H, m), 4.12 (1 H, app. t, J = 8 Hz),
3.35–3.06 (4 H), 2.64 (1 H, m), 2.38 (1 H, m), 1.65 (1 H, m), 1.52
(1 H, m), 1.45–1.35 (4 H), 0.90 (3 H, t, J = 6.9 Hz).
5-Benzyl-2-phenyltetrahydroisoxazolo[2,3-a]pyrazin-4-one
(13)
The product was purified by chromatography (EtOAc–hexane,
75:25) to give 13.
13C NMR (CDCl3): d = 168.3, 136.1, 128.6, 127.9, 127.5, 76.6, 63.9,
49.4, 47.8, 42.6, 38.8, 34.6, 27.9, 22.4, 13.8.
Yield: 270 mg (87%); off-white solid; Rf ca. 0.38 in EtOAc; mp
94.5–96.0 °C.
MS (CI; CH4): m/z (%) = 289 (100), 203 (27).
HRMS (TOF ESI+): m/z calcd for C17H24N2O3 (+H): 289.1910;
found: 289.1903.
IR (KBr): 3437, 3031, 1635, 1497, 1260, 747, 698 cm–1.
1H NMR (CDCl3): d = 7.38–7.26 (10 H), 5.24 (1 H, dd, J = 6.1, 8.3
Hz), 4.69 (1 H, d, J = 14.5 Hz), 4.59 (1 H, d, J = 14.6 Hz), 4.30 (1
H, dd, J = 6.8, 8.3 Hz), 3.46 (1 H, m), 3.35–3.25 (3 H, m), 3.04 (1
H, ddd, J = 6.5, 8.5, 12.9 Hz), 2.74 (1 H, ddd, J = 6.1, 8.6, 12.9 Hz).
13C NMR (CDCl3): d = 168.1, 141.1, 136.2, 128.8, 128.6, 128.1,
127.9, 127.7, 126.1, 78.2, 64.3, 49.7, 48.2, 42.6, 42.0.
5-Benzyl-2-hydroxymethyltetrahydroisoxazolo[2,3-a]pyrazin-
4-one (17a) and 5-Benzyl-2-hydroxymethyltetrahydroisoxazo-
lo[2,3-a]pyrazin-4-one (17b)
The crude product was purified eluting with EtOH–EtOAc (10:90)
to separate the two diastereomers.
MS (CI; CH4): m/z (%) = 309 (100).
Compound 17a
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C,
73.97; H, 6.68; N, 9.07.
Yield: 222 mg (85%); tan solid; Rf ca. 0.21 in EtOAc; mp 129–
131 °C.
IR (KBr): 3204, 2929, 1646, 1492, 1449, 1352, 1260, 1092, 748,
700 cm–1.
1H NMR (CDCl3): d = 7.37–7.22 (5 H), 4.60 (2 H, s), 4.35 (1 H, m),
4.10 (1 H, dd, J = 5.9, 8.7 Hz), 3.73 (1 H, dd, J = 2.7, 11.9 Hz), 3.62
(1 H, dd, J = 5.0, 11.7 Hz), 3.49 (1 H, m), 3.25–3.15 (3 H), 2.64 (2
H, m), 1.32 (1 H, br s).
5-Benzyl-2-(4-methoxyphenyl)tetrahydroisoxazolo[2,3-a]pyr-
azin-4-one (14)
Crude product was chromatographed (EtOAc–hexane, 75:25) to
give 14.
Yield: 300 mg (90%); off-white solid; Rf ca. 0.34 in EtOAc; mp
106.0–107.5 °C.
13C NMR (CDCl3): d = 168.3, 135.2, 128.8, 128.0, 127.8, 77.1, 64.5,
63.8, 49.7, 42.6, 42.0 35.0.
IR (KBr): 3432, 2930, 1638, 1514, 1493, 1251, 1174, 1031, 834,
698 cm–1.
MS (CI; CH4): m/z (%) = 263 (100).
1H NMR (CDCl3): d = 7.38–7.25 (7 H), 6.89 (2 H, br d, J = 8.8 Hz),
5.19 (1 H, dd, J = 6.7, 8.4 Hz), 4.70 (1 H, d, J = 14.4 Hz), 4.58 (2
H, d, J = 14.4 Hz), 4.32 (1 H, br d, J = 7.7 Hz), 3.80 (3 H, s), 3.43
(1 H, m), 3.35–3.21 (3 H), 2.98 (1 H, ddd, J = 6.7, 8.3, 12.8 Hz),
2.72 (1 H, ddd, J = 6.2, 8.5, 12.7 Hz).
13C NMR (CDCl3): d = 168.2, 159.4, 136.2, 132.8, 128.8, 128.1,
127.8, 127.6, 114.0, 78.0, 64.6, 55.3, 49.7, 48.2, 42.6, 41.9.
HRMS (TOF ESI+): m/z calcd for C14H18N2O3 (+H): 263.1390;
found: 263.1389.
Compound 17b
Yield: 17.7 mg (7%); slightly yellow oil; Rf ca. 0.71 in EtOAc. By
1H NMR, the sample contained 5% (ca.1 mg) of diastereomer 17a.
IR (KBr): 3403, 2925, 1637, 1496, 1453, 1355, 731 cm–1.
MS (CI; CH4): m/z (%) = 339 (100).
1H NMR (CDCl3): d = 7.36–7.23 (5 H), 4.70 (1 H, d, J = 14.6 Hz),
4.50 (1 H, d, J = 14.6 Hz), 4.20 (1 H, m), 4.11 (1 H, dd, J = 5.6, 8.7
Hz), 3.77 (1 H, dd, J = 2.9, 12.2 Hz), 3.58 (2 H, m), 3.39–3.21 (2
H), 3.10 (1 H, m), 2.72 (1 H, m), 1.87 (1 H, br s).
13C NMR (CDCl3): d = 168.7, 136.2, 128.7, 128.1, 127.7, 78.5, 63.4,
63.2, 50.0, 48.3, 41.7, 35.2.
Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C,
70.75; H, 6.69; N, 8.08.
2,5-Dibenzyltetrahydroisoxazolo[2,3-a]pyrazin-4-one (15)
The product was purified by chromatography (EtOAc–hexane,
75:25) to give 15.
MS (CI; CH4): m/z (%) = 263 (100).
Yield: 294 mg (91%); off-white solid; Rf ca. 0.40 in EtOAc; mp
92.0–93.5 °C.
5-Benzyl-2-(2-hydroxyethyl)tetrahydroisoxazolo[2,3-a]pyr-
azin-4-one (18a) and 5-Benzyl-2-(2-hydroxyethyl)tetrahydro-
isoxazolo[2,3-a]pyrazin-4-one (18b)
The crude product was eluted with EtOH–EtOAc (10:90, then
20:80) to separate the diastereomers. The combined mixed fractions
were rechromatographed using EtOH–EtOAc (15:85).
IR (KBr): 3437, 2929, 1634, 1498, 1453, 1259, 1073, 701 cm–1.
1H NMR (CDCl3): d = 7.35–7.19 (10 H), 4.66 (1 H, d, J = 14.7 Hz),
4.48 (1 H, d, J = 14.7 Hz), 4.48 (1 H, m), 4.08 (1 H, app. t, J = 7.7
Hz), 3.36–3.17 (4 H), 3.10 (1 H, m), 2.99 (1 H, dd, J = 6.5, 13.8
Hz), 2.80 (1 H, dd, J = 6.5, 13.8 Hz), 2.66–2.46 (2 H).
13C NMR (CDCl3): d = 168.2, 137.6, 136.2, 129.4, 128.7, 128.5,
128.0, 127.7, 126.6, 77.5, 64.0, 49.6, 48.0, 42.7, 41.1, 38.4.
Synthesis 2005, No. 3, 465–469 © Thieme Stuttgart · New York

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Diastereoselectivity in the Cycloaddition of 1-Benzyl-2-piperazinone Nitrone with Alkenes
469
Compound 18a
13C NMR (CDCl3): d = 169.1, 136.3, 128.7, 128.1, 127.7, 81.9, 70.0,
Yield: 251 mg (91%); waxy, off-white solid; Rf ca. 0.42 in EtOH–
EtOAc (20:80); mp 81.5–82.5 °C.
IR (KBr): 3467, 1643, 1494, 1258, 1052, 1032, 704 cm–1.
63.9, 50.2, 47.4, 41.6, 41.1, 22.3.
MS (CI; CH4): m/z (%) = 277 (100).
Compound 19b
1H NMR (CDCl3): d = 7.35–7.22 (5 H), 4.64 (1 H, d, J = 14.5 Hz),
4.56 (1 H, d, J = 14.5 Hz), 4.46 (1 H, m), 4.13 (1 H, dd, J = 6.4, 8.8
Hz), 3.77 (2 H, br m), 3.41 (1 H, m), 3.26–3.12 (3 H), 2.73 (1 H,
ddd, J = 6.2, 8.1, 12.7 Hz), 2.48 (1 H, ddd, J = 5.5, 8.9, 12.9 Hz),
2.30 (1 H, br s), 1.86 (2 H, m).
13C NMR (CDCl3): d = 168.3, 136.2, 128.8, 128.0, 127.7, 75.2, 63.7,
60.0, 49.7, 47.8, 42.3, 38.9, 37.4.
Yield: 217 mg (79%); waxy, slightly orange solid; Rf ca. 0.21 in
EtOAc; mp 89–91 °C.
IR (KBr): 3396, 1617, 1498, 1048, 698 cm–1.
1H NMR (CDCl3): d = 7.36–7.23 (5 H), 4.71 (1 H, d, J = 14.3 Hz),
4.48 (1 H, d, J = 14.3 Hz), 4.18 (1 H, app. t, J = 7.0 Hz), 3.57–3.43
(3 H), 3.34–3.22 (2 H), 3.15 (1 H, m), 2.68 (1 H, dd, J = 6.4, 12.5
Hz), 2.39 (1 H, dd, J = 8.1, 12.6 Hz), 1.84 (1 H, br s), 1.29 (3 H, s).
MS (CI; CH4): m/z (%) = 277 (100), 203 (32).
13C NMR (CDCl3): d = 168.5, 136.2, 128.8, 128.2, 127.8, 83.3, 67.1,
64.2, 49.9, 48.5, 42.0, 40.7, 23.6.
HRMS (TOF ESI+): m/z calcd for C15H20N2O3 (+H): 277.1547;
found: 277.1541.
MS (CI; CH4): m/z (%) = 277 (100).
Compound 18b
Anal. Calcd for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14. Found: C,
64.89; H, 7.31; N, 10.20.
Yield: 11.1 mg (4%); slightly orange oil; Rf ca. 0.28 in EtOH–
EtOAc (20:80). By 1H NMR, the sample contained 10% ca. 1 mg)
of diastereomer 18a.
IR (CHCl3): 4311, 1632, 730, 705 cm–1.
References
1H NMR (CDCl3): d = 7.37–7.23 (5 H), 4.61 (2 H, s), 4.20 (1 H, m),
4.09 (1 H, dd, J = 5.4, 9.0 Hz), 3.72 (2 H, br t, J = 5.9 Hz), 3.63 (1
H, ddd, J = 3.9, 9.3, 12.9 Hz), 3.36 (1 H, app. dt, J = 4.0, 13.6 Hz),
3.26 (1 H, ddd, J = 4.1, 9.4, 13.5 Hz), 3.07 (1 H, dt, J = 4.2, 12.0
Hz), 2.87 (1 H, ddd, J = 7.3, 9.0, 12.9 Hz), 2.25 (1 H, ddd, J = 5.4,
8.3, 12.7 Hz), 1.94–1.74 (2 H), 1.68 (1 H, br s).
13C NMR (CDCl3): d = 169.1, 136.3, 128.7, 128.1, 127.7, 76.6 (co-
incident with the upfield line of CDCl3), 63.0, 60.5, 50.1, 48.3, 41.5,
40.0, 37.2.
(1) Current address: Wyeth Pharmaceuticals, 500 Arcola Road,
Collegeville, PA 19426, USA.
(2) For reviews of nitrone cycloaddition reactions and their
application to organic synthesis see: (a) Confalone, P. N.;
Huie, E. M. Org. React. (N. Y.) 1988, 36, 1. (b) Jones, R. C.
F.; Martin, J. N. in Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products, 59; Padwa, A.; Pearson, W. H., Eds.; Wiley: New
York, 2002, 1–81.
(3) Bernotas, R. C.; Thomas, C. E.; Carr, A. A.; Nieduzak, T. R.;
Adams, G.; Ohlweiler, D. F.; Hay, D. A. Bioorg. Med.
Chem. Lett. 1996, 6, 1105.
MS (CI; CH4): m/z (%) = 277 (100), 203 (80).
5-Benzyl-2-hydroxymethyl-2-methyltetrahydroisoxazolo[2,3-
a]pyrazin-4-one (19a) and 5-Benzyl-2-hydroxymethyl-2-meth-
yltetrahydroisoxazolo[2,3-a]pyrazin-4-one (19b)
(4) Bernotas, R. C.; Adams, G. Tetrahedron Lett. 1996, 37,
7339.
(5) Bernotas, R. C.; Adams, G. Tetrahedron Lett. 1996, 37,
7343.
The crude product was purified eluting with EtOH–EtOAc (10:90).
(6) For a discussion of the stereochemistry of alkene–cyclic
nitrone reactions, see: Tufariello, J. T. Acc. Chem. Res. 1979,
12, 396.
(7) Tufariello, J. J.; Ali, S. A. J. Am. Chem. Soc. 1979, 101,
7114.
Compound 19a
Yield: 31.1 mg (11%); slightly orange solid; Rf ca. 0.18 in EtOAc;
mp 102–104 °C (softened at ca. 85 °C).
IR (KBr): 3416, 1648 cm–1.
(8) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Masanori, S. Chem. Commun. 1996, 1861.
(9) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.;
Watanabe, S. J. Org. Chem. 1990, 55, 1736.
(10) Little, R. D. in Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M., Ed.; Pergamon Press: New York, 1991, Chap.
3.1.
1H NMR (CDCl3): d = 7.37–7.23 (5 H), 4.69 (1 H, d, J = 14.6 Hz),
4.57 (1 H, d, J = 14.6 Hz), 4.07 (1 H, dd, J = 3.2, 9.0 Hz), 3.74 (1
H, m), 3.56 (2 H, s), 3.40 (1 H, app. dt, J = 3.2, 14.2 Hz), 3.24 (1 H,
ddd, J = 4.4, 10.5, 14.0 Hz), 3.02 (1 H, ddd, J = 2.8, 4.4, 12.2 Hz),
2.80 (1 H, dd, J = 9.1, 13.0 Hz), 2.47 (1 H, dd, J = 3.2, 12.9 Hz),
1.72 (1 H, br s), 1.23 (3 H, s).
(11) Kane, J. M.; Carr, A. A. Tetrahedron Lett. 1980, 21, 3019.
Synthesis 2005, No. 3, 465–469 © Thieme Stuttgart · New York